Gene therapy holds great promise as a clinical treatment for a variety of human maladies. Gene therapy involves the delivery of an exogenous gene or other polynucleotide to a cell or plurality of cells. The exogenous gene carries the therapy in the sense that it is a composition that will, by way of its introduction into the cell, confer benefits onto the cell and/or host. The benefits conferred onto the cell are typically designed to be therapeutic to the host. Thus, the benefits are typically designed to correct a deficiency or to kill an undesirable cell.
Many different therapeutic strategies for gene therapy have been devised. In one approach, a natural gene that is defective for one reason or another is replaced with an exogenous copy of the gene that is more suitable for achieving the function and/or purpose of the gene. For example, a wild-type exongenous gene can be introduced as a replacement for a mutant, less effective natural gene. This approach holds promise for disease conditions in which an individual produces ineffective gene products, such as cystic fibrosis.
In another approach, a special gene, frequently referred to as a “suicide gene”, is delivered to one or more cells of interest. The suicide gene encodes a gene product that is toxic to the cell. Accordingly, production of the suicide gene product ultimately leads to the death of the cell. This approach holds promise for treatment of disease conditions in which it is desirable to eliminate certain cells from a host, such as in various forms of cancer.
In both of these approaches, delivery of the exogenous gene to the cells of interest presents a challenge. Frequently, a vector of some type is used to deliver the gene to the cells or tissue being treated. For several reasons, viral vectors are currently the most frequently used vector in gene therapy procedures. The natural replication cycle of a virus enables the vector to reproduce its genetic contents, including any exogenous genes, using the molecular machinery of an infected cell. Subsequently, the infected cell releases the resultant daughter vectors to the surrounding environment. This allows the exogenous gene to be repeatedly introduced into new cells, thereby expanding the area in which the therapy occurs beyond the originally infected cell.
Some benefits of using a viral vector are lost, however, when a suicide gene is utilized. By nature, the suicide gene encodes a product that is toxic to the cell. Thus, the gene encodes a product that will ultimately kill the cell. If the suicide gene is sufficiently toxic, the cell may perish before the vector is able to replicate and repackage itself for delivery to other cells. As a result, the distribution of the therapy, i.e., the suicide gene, can be stopped prior to expansion beyond the original cells, which may decrease the effectiveness of the therapy.
Some toxins, such as the shiga, cholera, and diptheria toxins, appear to be sufficiently toxic to create this situation. Indeed, elaborate molecular “choke” mechanisms have been used to slow the production of the suicide gene product in order to allow production and packaging of viral components.